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American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2011; 156B(8):989-91. · 3.70 Impact Factor
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ABSTRACT: D(2)-like antagonists potentiate dopamine release. They also inhibit dopamine uptake by a mechanism yet to be clarified. Here, we monitored dopamine uptake in the striatum of anesthetized mice. The dopamine overflow was evoked by brief electrical stimulation of the medial forebrain bundle (four pulses at 100 Hz) and was monitored with carbon fiber electrodes combined with continuous amperometry. The decay phase of evoked overflows reflects dopamine half-life, which entirely depends on uptake. The D(2)-like antagonists haloperidol and eticlopride enhanced the half-life by 45% and 48%, respectively, a moderate effect as compared to the uptake blocker nomifensine (528%). Both D(2)-like antagonists did not affect dopamine uptake in mice lacking D(2) receptors. Inhibition of tonic dopamine release by gamma-butyrolactone did not mimic the enhancing effect of D(2) antagonists on dopamine half-life. However, prolonged stimulation boosted dopamine uptake and this effect was not observed after haloperidol treatment or in mice lacking D(2) receptors. Therefore, dopamine uptake is accelerated in conditions of excessive D(2) stimulation but not finely tuned in resting conditions. Inhibition of dopamine uptake by D(2) antagonists synergizes with the potentiation of dopamine release to strongly alter the phasic dopamine signaling.
Journal of Neurochemistry 02/2011; 116(3):449-58. · 4.06 Impact Factor
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ABSTRACT: There is often a huge gap between neurobiological facts and firm conclusions stated by the media. Data misrepresentation in the conclusions and summaries of neuroscience articles might contribute to this gap.
Using the case of attention deficit hyperactivity disorder (ADHD), we identified three types of misrepresentation. The first relies on prominent inconsistencies between results and claimed conclusions and was observed in two scientific reports dealing with ADHD. Only one out of the 61 media articles echoing both scientific reports adequately described the results and, thus questioned the claimed conclusion. The second type of misrepresentation consists in putting a firm conclusion in the summary while raw data that strongly limit the claim are only given in the results section. To quantify this misrepresentation we analyzed the summaries of all articles asserting that polymorphisms of the gene coding for the D4 dopaminergic receptor are associated with ADHD. Only 25 summaries out of 159 also mentioned that this association confers a small risk. This misrepresentation is also observed in most media articles reporting on ADHD and the D4 gene. The third misrepresentation consists in extrapolating basic and pre-clinical findings to new therapeutic prospects in inappropriate ways. Indeed, analysis of all ADHD-related studies in mice showed that 23% of the conclusions were overstated. The frequency of this overstatement was positively related with the impact factor of the journal.
Data misrepresentations are frequent in the scientific literature dealing with ADHD and may contribute to the appearance of misleading conclusions in the media. In synergy with citation distortions and publication biases they influence social representations and bias the scientific evidence in favor of the view that ADHD is primarily caused by biological factors. We discuss the social consequences and the causes of data misrepresentations and suggest a few corrective actions.
PLoS ONE 01/2011; 6(1):e14618. · 4.09 Impact Factor
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ABSTRACT: In Parkinson's disease dopamine depletion imbalances the two major output pathways of the striatum. L-DOPA replacement therapy is believed to correct this imbalance by providing effective D1 and D2 receptor stimulation to striatonigral and striatopallidal neurons, respectively. Here we tested this assumption in the rat model of Parkinsonism by monitoring the spike response of identified striatal neurons to cortical stimulation. As predicted, in 6-hydroxydopamine lesioned rats we observed that L-DOPA (6 mg/kg + benserazide), apomorphine and the D2 agonist quinpirole (0.5 mg/kg i.p.) counteract the enhanced responsiveness of striatopallidal neurons. Unexpectedly, the depressed responsiveness of striatonigral neurons was corrected by quinpirole whereas D1 stimulation exerted no (apomorphine, cPB) or worsening effects (L-DOPA, SKF38393 10 mg/kg). Therefore, quinpirole, but not D1 stimulation, restores functional equilibrium between the two striatal output pathways. Our results might explain the therapeutic effect of D2-based medications in Parkinson's disease.
Neurobiology of Disease 07/2009; · 5.40 Impact Factor
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ABSTRACT: The striatum is the main input structure of the basal ganglia (BG) [1]. Because it receives massive excitatory inputs from
the cortex and mainly projects to deeper BG nuclei, the treatment and transmission of cortical inputs by striatal neurons
represent a crucial step in the cortex–BG–thalamus feedback loops. Moreover, the striatum is the brain area that is the most
densely innervated by dopaminergic terminals. Because Parkinson's disease is characterized by a severe degeneration of dopaminergic
neurons, it is crucial to understand how the dopamine (DA) depletion affects the transfer of information from the cortex to
the BG via the striatum. In this chapter we will review recent in vivo studies addressing these questions. However, in vitro
studies investigating the corticostriatal transmission are not deeply discussed here because others review them elsewhere
in this book.
12/2008: pages 157-169;
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Francois Gonon
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ABSTRACT: Although psychostimulants alleviate the core symptoms of attention-deficit/hyperactivity disorder (ADHD), recent studies confirm that their impact on the long-term outcomes of ADHD children is null. Psychostimulants enhance extracellular dopamine. Numerous review articles assert that they correct an underlying dopaminergic deficit of genetic origin. This dopamine-deficit theory of ADHD is often based upon an overly simplistic dopaminergic theory of reward. Here, I question the relevance of this theory regarding ADHD. I underline the weaknesses of the neurochemical, genetic, neuropharmacological and imaging data put forward to support the dopamine-deficit hypothesis of ADHD. Therefore, this hypothesis should not be put forward to bias ADHD management towards psychostimulants.
Trends in Neurosciences 12/2008; 32(1):2-8. · 14.23 Impact Factor
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ABSTRACT: Striatonigral and striatopallidal neurons form distinct populations of striatal projection neurons. Their discharge activity is imbalanced after dopaminergic degeneration in Parkinson's disease. Striatal projection neurons receive massive cortical excitatory inputs from bilateral intratelencephalic (IT) neurons projecting to both the ipsilateral and contralateral striatum and from collateral axons of ipsilateral neurons that send their main axon through the pyramidal tract (PT). Previous anatomical studies in rats suggested that IT and PT inputs preferentially excite striatonigral and striatopallidal neurons, respectively. Here we used electrophysiological criteria to identify them with antidromic stimulations. We show that the spontaneous discharge activity of IT neurons is depressed, whereas that of PT neurons is not affected in the rat cortex ipsilateral to 6-hydroxydopamine injection. However, our functional experiments do not support the hypothesis of a differential cortical input to striatal pathways. Firstly, although the conduction velocity of PT neurons is 4.6 times faster than that of IT neurons, identified striatopallidal and striatonigral neurons exhibit identical latencies of their spike responses to electrical stimulation of the ipsilateral cortex. Secondly, although PT neurons are ipsilateral, both striatal populations exhibit similar sensitivity to the stimulation of the ipsilateral and contralateral cortex. We suggest that IT neurons provide the main excitatory input to both striatal populations and that the corticostriatal PT input is weaker. Therefore, our functional data do not support our previous hypothesis that the deficit of IT neurons associated with the dopaminergic depletion might contribute to the striatal imbalance. This imbalance might rather result from intrinsic striatal mechanisms.
European Journal of Neuroscience 06/2008; 27(9):2313-21. · 3.63 Impact Factor
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ABSTRACT: Modulation of protein phosphorylation by dopamine is thought to play an important role in drug reward. Protein phosphatase-1 (PP-1) is known to mediate some of the changes in neuronal signaling that occur following activation of the dopaminergic system.
Two endogenous inhibitors of PP-1 are dopamine and cyclic 3', 5' adenosine monophosphate-regulated phosphoprotein (DARPP-32) and Inhibitor-1 (I-1). Knockout mice lacking one or both of these PP-1 inhibitors were tested for responses to cocaine using in vivo amperometry and conditioned place preference.
Presynaptic dopaminergic function appears to be unaffected by these mutations because stimulation-evoked changes in extracellular dopamine levels were unchanged between wild type mice and mice lacking one or both of these PP-1 inhibitors. In contrast, conditioned place preference to cocaine is reduced in mice lacking DARPP-32, I-1, or both phosphoproteins. This does not appear to be due to a learning deficit because mice lacking both DARPP-32 and I-1 show normal passive avoidance learning.
These data imply that increased PP-1 function as a result of deficits in DARPP-32 or I-1 is sufficient to decrease the rewarding properties of cocaine. Furthermore, the mechanism for this altered cocaine place preference does not involve alteration of dopamine release or reuptake.
Biological Psychiatry 05/2002; 51(8):612-20. · 8.28 Impact Factor
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ABSTRACT: An increase of extracellular dopamine (DA) concentration is a major neurobiological substrate of the addictive properties of drugs of abuse. In this article we investigated the contribution of the DA D2 receptor (D2R) in the control of this response. Extracellular DA levels were measured in the striatum of mice lacking D2R expression (D2R-/-) by in vivo microdialysis after administration of the psychostimulant cocaine and the opioid morphine. Interestingly, the increase in extracellular DA induced by both drugs was strikingly higher in D2R-/- than in wild-type littermates. This indicates that D2Rs play a key role in the modulation of DA release in response to drugs of abuse. Furthermore, this observation prompted us to investigate the dopaminergic autoreceptor function in the absence of D2 receptor in D2R-/- mice. Results obtained using complementary microdialysis and voltammetry analyses show that the autoreceptor function regulating DA release is totally abolished in the absence of D2R, despite unchanged DA uptake and basal DA efflux. Finally, we propose that the short isoform D2S receptor of the D2 receptors is the one controlling change in DA release induced by drugs of abuse. Indeed, the neurochemical effects of cocaine and morphine are unchanged in animals with a selective deletion of the long isoform D2L receptor. Thus, deregulated expression of D2R isoforms might be involved in the vulnerability of an individual to drug abuse.
Journal of Neuroscience 05/2002; 22(8):3293-301. · 7.11 Impact Factor
